1. Field of the Invention
The present invention relates to novel aspartyl dipeptide ester derivatives, a sweetener and products such as foods which contain the sweetener.
2. Discussion of the Background
Fatness caused by excessive intake of sugar and diseases accompanied by fatness have been at issue in recent years, as eating habits have improved. Accordingly, a low-calory sweetener that replaces sugar has been in demand. Aspartame is a widely used sweetener which has excellent safety and taste properties. However, aspartame is not very stable.
WO 94/1139 discloses that derivatives having an alkyl substituted amino group in aspartic acid exhibit improved sweetening potency and slightly improved stability. The best compound described in this document is N-[N-(3,3-dimethylbutyl)-L-xcex1-aspartyl ]-L-phenylalanine 1-methyl ester having a 3,3-dimethylbutyl group as an alkyl group. The sweetening potency of this compound is 10,000 times that of sugar.
Other aspartame derivatives having 20 other types of substituents are described in above reference. However, their sweetening potency is reported to be less than 2,500 times that of sugar. Derivatives having a 3-(substituted phenyl)propyl group as an alkyl group are also disclosed. However, the sweetening potency of N-[N-(3-phenylpropyl)-L-xcex1-aspartyl ]-L-phenylalanine 1-methyl ester is 1,500 times and that of N-[N-[3-(3-methoxy-4-hydroxyphenyl)propyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester is 2,500 times that of sugar. Thus, their sweetening potency is far less than that of N-[N-(3,3-dimethylbutyl)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester (10,000 times). (U.S. Pat. No. 5,480,668 is the equivalent to WO 94/1139).
It is an object of the invention to provide novel aspartyl dipeptide ester derivatives which are safe and have a sweetening potency equal to or higher than that of the N-[N-(3,3-dimethylbutyl)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester.
It is another object of the present invention to provide a low-calory sweetener containing the novel derivatives as an active ingredient.
These and other objects are achieved according to the invention, the first embodiment of which includes a compound of Formula (1): 
wherein
R1, R2, R3, R4 and R5, independently represent a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms; or
R1 and R2, or R2 and R3 together form a methylenedioxy group, wherein R4, R5, and R1 or R3 which do not form said methylenedioxy group independently represent a substituent selected from the group consisting of a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms;
R6 represents a hydrogen atom or a hydroxyl group; and
R7 represents a substituent selected from the group consisting of a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a t-butyl group;
wherein R1 to R5 do not all represent hydrogen atoms; and
wherein R2 or R4 do not represent a methoxy group if R3 represents a hydroxyl group; and
the salt thereof.
In order to achieve above objects, the present inventors have synthesized several aspartame derivatives in which various 3-(substituted phenyl) propyl groups are introduced into an amino group of aspartic acid using cinnamaldehyde having various substituents and 3-phenylpropianaldehyde having various substituents.
The inventors have examined the sweetening potency of above aspartame derivatives. They have found that their sweetening potency is far higher than that of N-[N-(3-phenylpropyl)-L-xcex1-aspartyl]-L-phenylalanine-1-methyl ester and N-[N-(3,3-dimethylbutyl)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester. For example, N-[N-(3,3-dimethylbutyl)-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester has a sweetening potency of 10,000 times that of sugar and N-[N-(3-phenylpropyl)-L-xcex1-aspartyl]-L-phenylalanine-1-methyl ester has a sweetening potency of 1,500 times that of sugar (WO94/11391). The compounds represented by Formula (1), below, are excellent as a sweetener. These findings have led to the completion of the invention.
The novel aspartyl dipeptide ester derivatives of the invention include the compounds represented by Formula (1) and salts thereof. 
wherein
R1, R2, R3, R4 and R5, independently from each other, represent a substituent selected from a hydrogen atom (H), a hydroxyl group (OH), an alkoxy group (OR; methoxy group, ethoxy group, propoxy groups, or the like) having from 1 to 3 carbon atoms, an alkyl group (R; methyl group, ethyl group, propyl groups, or the like) having from 1 to 3 carbon atoms and a hydroxyalkyloxy group (for example, O(CH2)2OH or OCH2CH(OH)CH3) having 2 or 3 carbon atoms, or
R1 and R2, or R2 and R3 together form a methylenedioxy group (OCH2O);
wherein R4, R5 and, R1 or R3 which does not form the methyl enedioxy group as a part thereof, independently from each other, represent any substituents as mentioned above designated for the R1, R3, R4 and R5, respectively, provided the case where R1 to R5 are all hydrogen atoms and the case where R2 is a methoxy group and R3 is a hydroxyl group and the case where R4 is a methoxy group and R3 is a hydroxyl group are excluded,
R6 represents a hydrogen atom or a hydroxyl group, and
R7 represents a substituent selected from a methyl group (CH3), an ethyl group (CH2CH3), an isopropyl group (CH(CH3)2, an n-propyl group (CH2CH2CH3) and a t-butyl group (C(CH3)3).
Amino acids constituting the derivatives are preferably L-isomers since L-isomers are present in nature.
With respect to the compounds of the invention, the following inventions are preferably included.
[1] Compounds of Formula (1)
wherein R3 is a substituent selected from a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms,
R1, R2, R4 and R5 are, independently from each other, each a substituent selected from a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms, or
R1 and R2, or R2 and R3 together form a methylenedioxy group (OCH2O)
wherein R4, R5 and, R1 or R3 which does not form the methylenedioxy group as a part thereof, independently from each other, represent any substituents as mentioned above for the R1, R3, R4 and R5;
R6 is a hydrogen atom or a hydroxyl group, and
R7 is a substituent selected from a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a t-butyl group.
[2] Compounds of Formula (1)
wherein R3 is a hydrogen atom,
R1, R2, R4 and R5 are, independently from each other, each a substituent selected from a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms, or
R1 and R2, or R2 and R3 together form a methylenedioxy group (OCH2O)
wherein R4, R5 and, R1 or R3 which does not form the methylenedioxy group as a part thereof, independently from each other, represent any substituents as mentioned above designated for the R1, R3, R4 and R5, respectively,
R6 is a hydrogen atom or a hydroxyl group, and
R7 is a substituent selected from a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a t-butyl group.
[3] Compounds of Formula (1)
wherein R3 is a hydroxyl group,
R1, R2, R4 and R5 are each a substituent selected from a hydrogen atom, a hydroxyl group, an alkoxy group having from 1 to 3 carbon atoms, an alkyl group having from 1 to 3 carbon atoms and a hydroxyalkyloxy group having 2 or 3 carbon atoms, or
R1 and R2, or R2 and R3 together form a methylenedioxy group (OCH2O)
wherein R4, R5, and R1 or R3 which does not form the methylenedioxy group as a part thereof, independently from each other, represent any substituents as mentioned above designated for the R1, R3, R4 and R5, respectively,
R6 is a hydrogen atom or a hydroxyl group, and
R7 is a substituent selected from a methyl group, an ethyl group, an isopropyl group, an n-propyl group and a t-butyl group.
[4] Compounds of Formula (1)
wherein R2 is a hydroxyl group,
R3 is a methoxy group,
R1, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[5] Compounds of Formula (1) wherein
R2 and R3 are each a methoxy group,
R1, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[6] Compounds of Formula (1)
wherein R2 and R3 together form a methylenedioxy group,
R1, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[7] Compounds of Formula (1)
wherein R3 is a hydroxyl group,
R1, R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[8] Compounds of Formula (1)
wherein R3 is a methoxy group,
R1, R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[9] Compounds of Formula (1)
wherein R3 is an ethoxy group,
R1, R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[10] Compounds of Formula (1)
wherein R2 is a hydroxyl group,
R1, R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[11] Compounds of Formula (1)
wherein R2 is a methoxy group,
R1, R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[12] Compounds of Formula (1)
wherein R3 is a methoxy group,
R2 and R6 are each a hydroxyl group,
R1, R4 and R5 are each a hydrogen atom, and
R7 is a methyl group.
[13] Compounds of Formula (1)
wherein R1 is a hydroxyl group,
R3 is a methoxy group,
R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[14] Compounds of Formula (1)
wherein R1 is a hydroxyl group,
R2 is a methoxy group,
R3, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[15] Compounds of Formula (1)
wherein R1 is a hydroxyl group,
R4 is a methoxy group,
R2, R3, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[16] Compounds of Formula (1)
wherein R1 is a hydroxyl group,
R3 and R7 are each a methyl group, and
R2, R4, R5 and R6 are each a hydrogen atom.
[17] Compounds of Formula (1)
wherein R1 and R3 are each a methoxy group,
R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[18] Compounds of Formula (1)
wherein R1 is an ethoxy group,
R3 is a methoxy group,
R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[19] Compounds of Formula (1)
wherein R2 and R7 are each a methyl group,
R3 is a hydroxyl group, and
R1, R4, R5 and R6 are each a hydrogen atom.
[20] Compounds of Formula (1)
wherein R2 is a hydroxyl group,
R3 and R7 are each a methyl group, and
R1, R4, R5 and R6 are each a hydrogen atom.
[21] Compounds of Formula (1)
wherein R2 and R7 are each a methyl group,
R3 is a methoxy group, and
R1, R4, R5 and R6 are each a hydrogen atom.
[22] Compounds of Formula (1)
wherein R2 and R4 are each a methoxy group,
R1, R3, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[23] Compounds of Formula (1)
wherein R3 is a 2-hydroxyethoxy group,
R1, R2, R4, R5 and R6 are each a hydrogen atom, and
R7 is a methyl group.
[24] Compounds of Formula (1)
wherein R3 and R7 are each a methyl group, and
R1, R2, R4, R5 and R6 are each a hydrogen atom.
Preferred salts of the compounds of Formula (1) are, for example, salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; salts with amino acids such as lysine and arginine; salts with inorganic acids such as hydrochloric acid and sulfuric acid; and salts with organic acids such as citric acid and acetic acid; and salts with saccharin, acesulfame, cyclamic acid and glycyrrhizic (glycyrrhizinic) acid. These salts are included in the present invention.
The aspartyl dipeptide ester derivatives of the invention can easily be formed by reductively alkylating aspartame derivatives with cinnamaldehydes having various substituents and a reducing agent. Preferably, the reducing agent is a hydrogen/palladium carbon catalyst. Aspartame derivatives can be obtained by the usual peptide synthesis method (Izumiya et al., Basis of Peptide Synthesis and Experiments Thereof, Maruzen, published Jan. 20, 1985). Alternatively, the derivatives can be formed by subjecting aspartame derivatives (for example, xcex2-O-benzyl-xcex1-L-aspartyl-L-phenylalanine methyl ester) having a protective group in a carboxylic acid in the xcex2-position to reductive alkylation with cinnamaldehydes having various substituents and a reducing agent (for example, NaB(OAc)3H) (A. F. Abdel-Magid et al., Tetrahedron Letters, 31, 5595 (1990)), and then removing the protective group. However, the method of forming the compounds of the invention is not limited thereto. 3-Phenylpropionaldehydes having various substituents or acetal derivatives thereof can be used as precursor aldehydes in the reductive alkylation instead of cinnamaldehydes having various substituents.
As a result of a sensory evaluation, the compounds and the salts thereof in the invention were found to have a strong sweetening potency and have taste properties similar to that of sugar. For example, the sweetening potency of N-[N-[3(3-methyl-4-hydroxyphenyl)propyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester was approximately 35,000 times that of sugar; that of N-[N-[3-(2-hydroxy-4-methylphenyl)propyl]-L-xcex1-aspartyl]-L-xcex1-phenylalanine 1-methyl ester was approximately 30,000 times that of sugar; that of N-[N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester was approximately 20,000 times that of sugar; that of N-[N-[3-(2-hydroxy-4-methoxyphenyl)propyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester was approximately 20,000 times that of sugar; that of N-[N-[3-(3-hydroxy-4-methylphenyl)propyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester was approximately 15,000 times that of sugar; that of N-(N-(3-(3-hydroxyphenyl)propyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester was approximately 8,000 times that of sugar; that of N-[N-(3-(4-methoxyphenyl)propyl]-L-xcex1-aspartyl]-L-phenylalanine 1-methyl ester was approximately 6,500 times that of sugar; and that of N-(N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-L-xcex1-aspartyl]-L-tyrosine 1-methyl ester was approximately 16,000 times that of sugar.
The structures and the results of the sensory evaluation of aspartyl dipeptide derivatives represented by formula (2) are shown in Table 1. 
As demonstrated by the results of Table 1, the novel derivatives in the present invention are excellent in sweetening potency.
The compounds of the invention and their salts are used as a sweetener, singly or in combination with other sweeteners unless particular problems arise. The sweetening potency of the sweetener is preferably in the range of from 800 to 35,000 times that of sugar, and more preferably of from 15,000 to 35,000 times that of sugar. The sweetening potency includes all values and subvalues therebetween, especially including 1,000; 2,000; 3,000; 4,000; 5,000; 6,000; 7,000; 8,000; 9,000; 10,000; 11,000; 12,000; 13,000; 14,000; 15,000; 16,000; 17,000; 18,000; 19,000; 20,000; 21,000; 22,000; 23,000; 24,000; 25,000; 26,000; 27,000; 28,000; 29,000; 30,000; 31,000; 32,000; 33,000 and 34,000 times that of sugar.
When the derivatives of the invention are used as a sweetener, an appropriate carrier and/or an appropriate bulking agent may be used as required. Preferably, the carrier is water, sugar, saccharin or starch. It is preferred to select the bulking agent from water, sugar alcohol, polydextrose, sugar and starch.
The derivatives of the invention can be used as a sweetener or an ingredient therefor, and further as a sweetener for products such as foods and the like to which a sweetness has to be imparted. Example of such products are confectionery, chewing gum, hygiene products, toiletries, cosmetics, pharmaceutical products and veterinary products for animals. The pharmaceutical product is preferably a tablet or a medicated liquid. Still further, they can be used in a method of imparting a sweetness to the products. This method can be, for example, a conventional method for using a sweetening ingredient for a sweetener in the sweeteners or the method of imparting a sweetness. Preferably, the method includes mixing a product with the above sweetener. Preferably, the product is selected from a confectionery, a chewing gum, a hygiene product, a cosmetic article, a pharmaceutical product and a veterinary product Preferably, a carrier and/or bulking agent as above are added.